Abstract The aging population is rapidly expanding in our society, and sarcopenia contributes to physical frailty and cardiometabolic risks in elderly people. The age-related declines in muscle strength and mitochondrial function cannot be entirely explained by the respective decreases in muscle mass and mitochondrial content. We propose that these disproportionate effects are related to altered protein homeostasis. Increased oxidative damage to proteins and DNA occurs with age, and reduced muscle protein turnover and consequent accumulation of deleterious post-translational modifications may explain these results. We developed a novel method to determine the relative abundance of old (those synthesized earlier) to new (newly synthesized) proteins in specific protein pools. Using 2-dimensional gel electrophoresis, we observe trains of gel spots (gel spot isoforms) of the same protein. Gel spot isoforms correspond to the separation of a protein that has undergone modifications altering the isoelectric pH (pl) without substantially shifting its mass. Following in vivo metabolic labeling of proteins with a stable isotope of phenylalanine, different gel spot isoforms of an individual protein have widely variable isotopic enrichment. We find that a gel spot isoforms with greater modifications (e.g.; oxidation) also exhibit lower isotopic enrichment, indicating that these proteins were formed largely before the isotope infusion. We will determine if the relative accumulation of old and damaged proteins is higher in older people and if aerobic exercise training can accelerate the removal of old proteins and replacement with newly synthesized proteins by increasing protein synthesis and degradation. Since type II fiber atrophy occurs with age, we will determine whether synthesis rates of myosin heavy chain (MHC) isoforms IIa and IIx are altered with old age. We will also determine the effect of aerobic vs. resistance exercise training on synthesis rates of individual MHC isoforms and whether age affects the response to specific exercise programs. We will also contrast the effects of aerobic vs. resistance training on accumulation of old, modified proteins. The hypothesis is that aerobic exercise will replace damaged and old proteins with newly synthesized proteins whereas resistance exercise increases synthesis of specific contractile proteins with effect on replacing old and modified proteins. We will determine whether a combined exercise program increases synthesis of specific contractile proteins as well as removal of old and modified proteins. Additional mechanistic studies are planned to determine the relative impact of reactive oxygen species production and antioxidant defense system on protein modification. The proposed studies will for the first time determine whether age increases the relative composition of old and damaged isoforms of mitochondrial, myofibrillar, and sarcoplasmic proteins and a novel mechanism by which exercise programs correct the abnormality. The proposed studies will apply novel and innovative methodologies developed in our laboratory to address important mechanistic questions that may reveal potential therapeutic targets to combat sarcopenia.